Constitutive activation of STAT3 has been found in a wide variety of cancers, including breast cancer, sarcomas, and other cancers, promoting it as a very attractive therapeutic target. Cytokines, hormones, and growth factors binding to the cell surface receptors can activate the JAK-STAT signaling pathway. The receptors are activated and phosphorylated by JAK kinase(s). Subsequently, the STAT3 monomer is phosphorylated at Tyrosine705 (pTyr705) by the same kinases through its SH2 domain binding to pY loop of the activated receptors, leading to STAT3 homodimer through its SH2 dimerization. The dimerized STAT3 then translocates into the nucleus and binds to DNA, turning on a host of oncogenes. Altogether, these events such as cell proliferation and apoptosis resistance.
Several series of STAT3 dimerization inhibitors have previously been discovered via both computational and experimental methods. For example, phosphopeptide mimics were initially developed as STAT3 inhibitors to compete with the native phosphopeptide of the STAT3 protein. One specific example is PM-73G, a phosphopeptide mimic STAT3 inhibitor that can completely inhibit STAT3 Tyr705 phosphorylation at 0.5-1 μM level in various cancer cell lines (Mandal, P. K., et al. J. Med. Chem. 2011, 54, 3549-3563). Another phosphopeptide mimic, pCinn-Leu-cis-3,4-methanoPro-Gln-NHBn, has the lowest reported IC50 value at 69 μM, as determined by fluorescence polarization method (Mandal, P. K., et al. J. Med. Chem. 2009, 52, 6126-6141). Peptidomimetics have also been designed to target the STAT3 SH2 domain. Peptidomimetics are derived from phosphopeptides that mimic peptides but do not necessarily contain phosphate groups. For example, XZH-5 was designed using a structure-based approach to inhibit the formation of STAT3 dimers (Liu, A., et al., Cancer Sci. 102, 1381-1387; Liu, Y., et al. Apoptosis 16, 502-510). Various small molecules have also been reported to inhibit STAT3 dimerization, making them as more druggable candidates. STA-21 discovered by structure-based virtual screening was the first reported small inhibitor. It inhibits STAT3 dimerization, DNA binding, and STAT3-dependent luciferase reporter activity in breast cancer cells (Song, H., et al., Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 4700-4705). Another small molecule, Stattic, was discovered by high-throughput screening and has been shown to selectively inhibit activation, dimerization, and nuclear translocation of STAT3, increasing apoptosis in STAT3-dependent cancer cell lines (Schust, J., et al., Chem. Biol. 2006, 13, 1235-1242). Among all the reported nonpeptidomimetic small inhibitors, 5-hydroxy-9,10-dioxo-9,10-dihydroanthracene-1-sulfonamide (LLL12) has the lowest IC50 (0.16-3.09 μM; Lin, L., et al., Int. J. cancer. 2012, 130, 1459-69), inhibiting STAT3 phosphorylation and the growth of human cancer cells. However, so far, there are no FDA-approved STAT3-targeting drugs. Thus, the search for more druggable STAT3 inhibitors with higher potency and better bioavailability remains extremely important.
Accordingly, there is still a scarcity of compounds that are both potent, efficacious, and selective inhibitors of STAT3 and also effective in the treatment of diseases associated with STAT3 activity and diseases in which the STAT3 is involved. These needs and other needs are satisfied by the disclosed compounds, compositions, and methods herein.